Microglia RAGE exacerbates the progression of neurodegeneration within the SOD1G93A murine model of amyotrophic lateral sclerosis in a sex-dependent manner

Michael Maclean,Raquel López-Díez,Swetha Cuddapah,Ann Marie Schmidt,Jiyuan Hu,Henry H Ruiz,Judyta Juranek,Huilin Li,Paul F Gugger,Laura Frye

doi:10.1186/s12974-021-02191-2

Michael Maclean, Raquel López-Díez + Show 8 more

Open Access

https://doi.org/10.1186/s12974-021-02191-2

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Abstract

BackgroundBurgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The receptor for advanced glycation end products (RAGE) binds ligands relevant to ALS that accumulate in the diseased spinal cord and RAGE has been previously implicated in the progression of ALS pathology.MethodsWe generated a novel mouse model to temporally delete Ager from microglia in the murine SOD1G93A model of ALS. Microglia Ager deficient SOD1G93A mice and controls were examined for changes in survival, motor function, gliosis, motor neuron numbers, and transcriptomic analyses of lumbar spinal cord. Furthermore, we examined bulk-RNA-sequencing transcriptomic analyses of human ALS cervical spinal cord.ResultsTranscriptomic analysis of human cervical spinal cord reveals a range of AGER expression in ALS patients, which was negatively correlated with age at disease onset and death or tracheostomy. The degree of AGER expression related to differential expression of pathways involved in extracellular matrix, lipid metabolism, and intercellular communication. Microglia display increased RAGE immunoreactivity in the spinal cords of high AGER expressing patients and in the SOD1G93A murine model of ALS vs. respective controls. We demonstrate that microglia Ager deletion at the age of symptomatic onset, day 90, in SOD1G93A mice extends survival in male but not female mice. Critically, many of the pathways identified in human ALS patients that accompanied increased AGER expression were significantly ameliorated by microglia Ager deletion in male SOD1G93A mice.ConclusionsOur results indicate that microglia RAGE disrupts communications with cell types including astrocytes and neurons, intercellular communication pathways that divert microglia from a homeostatic to an inflammatory and tissue-injurious program. In totality, microglia RAGE contributes to the progression of SOD1G93A murine pathology in male mice and may be relevant in human disease.

Highlights

Burgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS)
Triggering receptor expressed on myeloid cells 2 (TREM2) has been implicated in the step-wise activation of microglia toward this disease-associated microglia (DAM) state; it is established that additional factors synergize or act independently of TREM2 in this “activation pathway” and that TREM2 plays complex pro- and anti-inflammatory effects in immune cells [23]
When we examined gene set differences in expression between the ALS patients and non-neurological controls with rotational gene set testing (ROAST) and competitive gene set testing (CAMERA) analyses, we observed significant enrichment of the “advanced glycation end product (AGE)-receptor for advanced glycation end products (RAGE) signaling pathway in diabetic complications” which was visualized by a barcode enrichment plot for the pathway (Fig. 1B, see Additional Files 1 and 2, Supplemental Table 1.11.3)

Summary

Introduction

Burgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Regardless of the underlying disease-related mutation, ALS is characterized by the accumulation of proteinaceous aggregates, which is associated with a pro-damage inflammatory and oxidative stress state involving multiple cell types. These processes collectively augur motor neuron death [2, 3]. While ALS results in motor neuron death, several landmark studies have elucidated critical roles for non-neuronal cells during disease progression [6,7,8,9,10,11] These considerations illustrate that ALS pathology is driven by dysfunction across a myriad of cell types whose intercommunications drive processes that irreparably damage neurons

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